Compound Collection

Our Stock Collection of about 200,000 compounds is the basis for all the department's projects on inhibitor development. The Collection is permanently updated with new compounds that synthesized in department's chemical laboratories. Major part of the Collection is heterocyclic compounds; the average number of rings in the structure of compounds is 3.3. The Collection comprises small subsets of many other organic compounds classes, such as phosphorganic, aliphatic, metalorganic. Since beginning till mid 2000s the Collection has been formed by combinatorial synthesis that has generated big clusters of structurally similar compounds. Then, due to directed chemical synthesis, a majority of singlets and small clusters has been formed. The Figure 1 shows the Collection growth since 2000.

Figure 1. Number of compounds in the Collection from 2000 to 2012.

74,5 % of compounds from the Collection satisfy Lipinski's Rule of Five. 50 % of compounds match lead-like criteria. These compounds have been selected to create separate libraries of drug-like and lead-like compounds that are used for screening projects. Quantitative distribution of physicochemical properties in the entire collection is shown in the Figures 2-5.

Figure 2. LogP distribution.

Figure 3. Molecular weight distribution.

Figure 4. Number of hydrogen acceptors distribution.

Figure 5. Number of hydrogen donors distribution

Reactive compounds and frequent hitters were removed from both drug-like and lead-like compound libraries. Reactive compounds (up to 16% of the total collection) have been separated in distinct library used in irreversible inhibitor search.

We have also created special compound collections such as blood-brain barrier permeable compound library, nature-like compound library, as well as target-specific libraries used in screening for inhibitors of protein kinases , GPCR's, ion channels etc. The computational part of the screening projects ("virtual screening") is performed either with receptor-based or ligand-based approach.

Most inhibitor search projects at our Department involve receptor-based virtual screening. For molecular docking we use famous software Autodock and DOCK. Much attention is paid to ligand pre-processing that is carried out with software developed in the Department. For virtual screening and other computationally expensive tasks we use cluster of 14 computer nodes. The most difficult stage of interpretation of docking results is carried out in several steps, using cutting-edge techniques in this field. Currently, for protein kinase inhibitors it is a combination of 3D-pharmacophore search and consensus scoring with visual inspection of the results (Figure 6). For example, hit rate for kinase inhibitors with IC50 <30 µM cutoff reaches 18%.

Figure 6. Virtual screening flowchart for protein kinase FGFR1.

After in vitro testing in our laboratory, the most promising compounds undergo structural optimization aimed at increasing inhibitory activity and improvement of ADME properties. In collaboration with other laboratories the compounds are tested using cell lines.